Initial Respiratory Support of Preterm Infants: The Role of CPAP, the INSURE Method, and Noninvasive Ventilation

Historical perspective

Based on the combined weight of multiple RCTs and their subsequent meta-analyses performed in the 1990s, surfactant was given as part of the initial resuscitation and management of preterm infants either at risk for or with evidence of respiratory distress syndrome (RDS). Available evidence led neonatologists to develop strong convictions that among infants who were intubated for respiratory distress, early surfactant administration was associated with decreased risk of pneumothorax (typical

Drawbacks of the conventional approach

Despite the well-documented benefits of surfactant replacement therapy, there are several negative aspects related to the way surfactant is administered and the subsequent respiratory management that follows. The act of placing an endotracheal tube (ETT) is invasive and may be traumatic. Laryngoscopy and intratracheal intubation is often unsuccessful⁴ and may cause hypoxemia, bradycardia, increased cranial pressure, systemic and pulmonary hypertension, and airway trauma.⁵ In part to avoid these

CPAP interfaces

CPAP has been successfully administered through a variety of methods. Although first administered for the treatment of RDS via ETT,¹² and later via only one naris through a modified ETT or single nasal prong, other superior interfaces have been developed and adopted. The most common interfaces in use today typically involve a nose mask or, more commonly, short bilateral nasal prongs. Distending pressure is generated either by simply placing the distal end of a CPAP circuit under a known depth

CPAP benefits

It is thought that CPAP assists the breathing of preterm infants in several ways. CPAP stents open the airways of preterm infants, which are characterized by their poor muscle tone and compliant structure. This effect reduces obstructive events that may translate to less apnea and less atelectasis.¹⁵ Animal models have demonstrated that CPAP causes a mechanical strain that is associated with accelerated lung protein accretion, lung growth, elastic recoil, and ultimately improved remodeling of

CPAP drawbacks

Pragmatically there are few problems with CPAP, mostly directly related to the CPAP interface. Given that the goal of CPAP is to provide continuous distending pressure that extends from the interface through the nasopharynx and the proximal airway and transmitted to the distal airways and alveoli, a tight seal must be maintained throughout. Leakage and the resultant pressure loss may occur at many points: from the CPAP system itself, out the mouth, or at the nasal interface. Chin straps may be

CPAP in the DR

Following the promising results of these early observational studies, several RCTs have been performed to address the question of whether the conventional approach of intubation and subsequent mechanical ventilation versus nasal CPAP is the superior approach for initial stabilization of the preterm infant at risk for developing RDS. The details of these studies are discussed later.

In 2004, Finer and colleagues¹⁹ reported the results of their feasibility study that examined whether initiating

Early CPAP versus standard care (intubation in DR and mechanical ventilation)

There are 3 large trials that examine the strategy of initial stabilization on nasal CPAP versus conventional management of intubation and surfactant administration in preterm infants (Table 1).

The CPAP Or nasal INtubation at birth (COIN) trial was a large RCT that compared CPAP versus early intubation among 610 preterm infants born between 25 + 0 and 28 + 6 weeks’ gestation.²¹ Only infants who exhibited some degree of respiratory distress but were spontaneously breathing at 5 minutes of life

A combined strategy: intubate, surfactant, and extubation

From the results of the COIN, SUPPORT, and VON DRM trials as well as the Rojas-Reyes meta-analysis, it is clear that initial stabilization on CPAP and provision of rescue surfactant only when necessary is at least as beneficial and quite possibly preferred over the standard therapy of intubation of all infants at risk in the DR and subsequent support with mechanical ventilation. However, the optimal respiratory care of newborns with RDS may involve yet another choice. Because mechanical

Early INSURE versus early CPAP as initial stabilization

Given that previous studies supported the concept that in preterm infants at risk of RDS prophylactic surfactant was more effective than rescue surfactant, An International Randomized Controlled Trial to Evaluate the Efficacy of Combining Prophylactic Surfactant and Early Nasal Continuous Positive Airway Pressure in Very Preterm Infants (CURPAP) trial was designed to evaluate early CPAP in the DR and early rescue surfactant for CPAP failures versus brief initial intubation, surfactant

Early INSURE versus standard care (intubation in DR and mechanical ventilation)

Little data are available that directly compare the INSURE method to the more conventional approach of intubation, prophylactic surfactant administration, and continued mechanical ventilation (Table 3). This lack of data may be partly caused by the observation that centers implementing INSURE strategies are heavily invested in CPAP as primary stabilization and have lost equipoise toward continued management on mechanical ventilation.

Tooley and Dyke³⁵ performed a pilot RCT that enrolled 42

Late INSURE

The earliest studies of the INSURE method did not test INSURE as part of the initial stabilization of high-risk infants but rather as rescue treatment for spontaneously breathing infants managed on CPAP with already established RDS. Verder and colleagues’31, 32 studies demonstrated that infants who were rescued with the INSURE strategy were less likely to need continued mechanical ventilation and that this effect was more pronounced if the treatment was applied earlier in the course of the

Late INSURE versus standard care (rescue surfactant and mechanical ventilation)

There are relatively few published reports comparing the use of the INSURE method later (>1 hour of life) in the course of established RDS to the standard approach of intubation, surfactant administration, and subsequent mechanical ventilation (Table 4). Each is discussed in detail next.

The VON has presented the results of a multicenter study randomizing 267 larger spontaneously breathing preterm infants (birth weight 1501–2500 g) with established RDS between 2 and 24 hours of life to either

Late INSURE versus continued CPAP

As previously noted, the first RCT of the INSURE method was Verder and colleagues’³² 1994 study performed in Scandinavia (Table 5). They enrolled 73 preterm infants (25–35 weeks’ gestational age) with moderate to severe distress on CPAP to either INSURE or to continued CPAP. Eligible infants already on CPAP with established RDS had to be at least 2 hours of age. The median time of randomization was 12 hours. The INSURE treatment was considered to have failed if extubation was not possible

Other studies featuring INSURE

The Texas Neonatal Research Group performed a multicenter trial that enrolled 132 larger (birth weight >1250 g) preterm (<36 weeks’ gestation) infants with RDS between 4 and 24 hours of life.⁴⁰ Unlike the previously discussed studies, infants were not required to be routinely stabilized on CPAP before the intervention, although approximately two-thirds in each group were managed in this fashion. Infants randomized to the INSURE arm were intubated and extubated unless the Fio₂ was higher than

Nasal intermittent positive pressure ventilation

Several studies have been performed examining the role of nasal intermittent positive pressure ventilation (NIPPV) as part of the initial stabilization of preterm infants. Although clinicians are increasingly trying to manage preterm infants without mechanical ventilation, the reality is that many preterm infants with RDS managed primarily on CPAP or extubated early to CPAP will fail, requiring intubation and stabilization on mechanical ventilation.19, 21, 43 NIPPV use in preterm infants is an

MIST and other methods of surfactant replacement

The benefits seen with the INSURE method are likely secondary to surfactant replacement among infants who are surfactant deficient, thereby establishing an adequate FRC. However, to facilitate this treatment, intubation and some brief period of positive pressure endotracheal ventilation is required. As previously noted, both intubation and mechanical ventilation can be associated with adverse outcomes. An alternative to the INSURE procedure has been developed and has been referred to by some as

Optimization of therapy

Independent of the strategy to stabilize preterm infants with or at risk for RDS, several adjunctive therapies have been associated with improved outcome. Antenatal steroid administration has a well-documented diminution of the risk of RDS and is likely synergistic when used with surfactant replacement, such as the INSURE method.³¹ This effect may also translate into a decreased risk in the development of CLD.⁵⁶ Caffeine prophylaxis has been proven to decrease apnea, decrease extubation

Summary

Despite the lack of definitive evidence of a single superior strategy, a groundswell is taking place toward noninvasive respiratory support. Several well-designed trials suggest that strategies, including application of CPAP in the DR or early in the course of RDS in preterm infants, are as safe and at least as effective as the standard approach of intubation in the DR. Although prophylactic surfactant does not offer any definite benefit over selective treatment, it should be given as early as